Deferiprone (DFP) Targets Cancer Stem Cell (CSC) Propagation by Inhibiting Mitochondrial Metabolism and Inducing ROS Production
Deferiprone (DFP) Targets Cancer Stem Cell (CSC) Propagation by Inhibiting Mitochondrial Metabolism and Inducing ROS Production
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DOI：
10.3390/cells9061529
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发表时间：
2020-06-01
期刊：
影响因子：
6
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
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作者：
Fiorillo, Marco;Toth, Fanni;Lisanti, Michael P.
去铁酮（DFP），也称为奥贝安可，是FDA批准的口服活性铁螯合剂，目前临床上用于治疗铁超载，特别是重型地中海贫血。由于铁是线粒体代谢功能绝对需要的Fe-S簇组装中的关键因素，因此我们假设DFP处理可用于选择性靶向癌症干细胞（CSC）中的线粒体。为此，我们使用两种ER（+）人乳腺癌细胞系，即MCF 7和T47 D细胞作为模型系统。更具体地，采用3D肿瘤球测定作为CSC活性的功能性读出，其测量在低附着条件下的锚定非依赖性生长。在这里，我们表明DFP剂量依赖性地抑制CSC的增殖，对于MCF 7的IC-50类似于100 nM，对于T47 D细胞的IC-50类似于0.5至1 μ M，使DFP成为迄今为止我们和其他人已经确定用于靶向CSC的最有效的FDA批准的药物之一。从机制上讲，我们表明高浓度的DFP代谢靶向MCF 7和T47 D细胞单层中的线粒体耗氧量（OCR）和糖酵解（细胞外酸化率（ECAR））。最重要的是，我们证明，DFP还诱导了活性氧（ROS）和线粒体超氧化物产生的普遍增加，其影响在N-乙酰半胱氨酸（NAC）的存在下逆转。因此，我们建议DFP是药物再利用和旨在根除CSC的II期临床试验的新候选治疗剂。
Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of similar to 100 nM for MCF7 and an IC-50 of similar to 0.5 to 1 mu M for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs.